FI87572B - FREQUENCY REFRIGERATION OF PLATINUM COMPLEX WITH THERAPEUTIC EFFECT - Google Patents

Description

87572

Process for the preparation of a therapeutically active platinum complex Förfarande för framställning av platinakomplex med 5 terapeutisk effekt

The invention relates to an analogous process for the preparation of a therapeutically active platinum complex of formula (I): wherein A and B are the same or different and each represents an amine group, or A and B together denote a diamino group. -C3_g-cycloalkyl group; 25 and Z represents a group of formula (II):

O

// O-C (CH2) n v 30 / \ / \

C CH-R1 (ID

\ / \ / Ο-c N-c w I w

O R2 O

or a group of formula (III): 35 2 87572 o // o-c / \ x cIII) \ /

5 N-C-H

I I

C-CH

R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group, a C 1 -C 1 alkoxy group, a substituted C 1 -C 1 alkyl group having at least one of the following substituents selected from hydroxy groups, silyloxy groups having 1 to 3 C 1 -C 4 alkyl substituents on the silicon atom, of C 1 -C 4 alkoxy groups, of the formulas -OPO (OR 3) 2, in which R 3 represents a C 1 -C 4 alkyl group or a phenyl group and -O-COR * - groups in which R * represents a C 1 -C 6 alkyl group, C 2 -C 5 alkoxyalkoxy groups and C 3 -C 7 alkoxyalkoxyalkoxy groups, R 2 represents a hydrogen atom, a C 1 -C 5 alkyl group, a substituted C 1 -C 4 alkyl group having at least one of the substituents selected from C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups, X represents a single carbon-carbon bond or a methylene group, n is 0 or 1

The present invention relates to a series of novel quadrico-coordinated divalent platinum complexes with certain specific amino compounds. Such complexes have valuable antitumor activity and better solubility than known antitumor platinum compounds and complexes. The invention also provides a process for preparing these complexes and methods and compositions for using them.

Cancer disorders are a major medical problem, but they 3,87572 are often difficult to cure. The main reason for this is that the differences between tumor cells and normal cells are usually extremely small, as a result of which compounds that are toxic to tumor cells are also toxic to normal cells. The treatment of cancerous disorders 5 therefore generally depends on very small differences in susceptibility between tumor cells and normal cells for antitumor agents.

Various platinum compounds are known to have antitumor activity. For example, cisplatin [Rosenberg et al., Nature 222. 385 (1965) and Merck Index, tenth edition (1983) monograph 2289] has been successfully used in the treatment of tumors and also Malo-nato (1,2-diaminocyclohexane) platinum (II) [ e.g., U.S. Patent 4,169,846 and Kidani et al., Gann, 71, 637-643 (1980)] have been proposed for such use. Both of the above platinum complexes have some structural similarity to the compounds of the invention. Another platinum complex that has recently entered tumor treatment, although structurally less similar to the compounds of the present invention, is carboplatin [Drugs of the Future, Vol. 8, no. 20 6, 489-491 (1983)]. However, most known platinum complexes, including those mentioned above, are strong renal toxins and poorly soluble in water, making it difficult to formulate them into a suitable dosage form.

Another platinum complex with limited structural similarity to the compounds of the present invention is disclosed in U.S. Patent Application 902,420, filed August 29, 1986.

We have now invented a new series of platinum complexes with good antitumor activity but relatively few side effects such as renal toxicity and bone marrow loss and good water solubility.

The invention provides a composition comprising an antitumor agent and a pharmaceutically acceptable carrier or diluent, wherein the antitumor agent is selected from the group consisting of compounds of formula (I).

4 H7572

The invention further provides a method of treating a tumor-suffering animal, preferably a mammal (including a human), comprising administering to said animal an effective amount of an antitumor agent, wherein the antitumor agent is selected from the group consisting of formula (I). compounds.

Thus, the invention provides methods for preparing therapeutically active compounds, as described in more detail below.

The compounds prepared by the process of the present invention contain a quadrico-coordinated, divalent platinum atom having amino groups derived at two coordinate positions derived from one diamino or two monoamino compounds (represented by A and B) and having carboxylic acid atoms and two amino coordinates at the other two coordinate positions. karboksihapplatomia.

A and B together may represent a diamino compound as defined above which is a diamino-C3-4 cyclohexyl group.

Each amino group is produced by an amino substituent on the alicyclic ring or a C 1 -C 4 aminoalkyl substituent on the alicyclic ring; if desired, the compound may contain two such amino substituents, two such aminoalkyl substituents or one such amino substituent and one such aminoalkyl substituent. In the case of aminoalkyl substituents, the alkyl moiety has 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, and most preferably one carbon atom. Examples of such aminoalkyl groups include aminomethyl-30-, 2-aminoethyl, 3-aminopropyl and 4-aminobutyl groups for which an aminomethyl group is recommended. The alicyclic ring system itself is preferably a cycloalkyl ring and may be a simple, optionally crosslinked ring, or may be provided by two fused rings, the total number of carbon atoms in the ring or in rings being 5-8. Examples of such ring systems include cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo- [2.1.1] hexane, 8,9,10-trinorkaran, 8,9,10-trinorpinane and 8,9,10-5,872 trinorbornane systems. , of which cyclohexane, cycloheptane, cyclooctane and bicyclo [2.1.1] hexane systems are recommended. Examples of such particularly preferred diamines include 1,1-bis [aminomethyl] cyclohexane, 1,2-diaminocyclopentane, 1-amino-5-aminomethylcyclopentane, 1,2-diaminocyclohexane, 1-amino-2-aminomethylcyclohexane, 1,2-diaminocycloheptane , 1,2-diaminocyclooctane and 2,3-diaminobicyclo [2.1.1] cyclohexane.

Compounds of the present invention wherein Z represents a group of formula (II) may be represented by formula (Ia):

O

// A 0-C (CH2) n \ / \ / ^

Pt C CH-R1 (Ia) 15 / \ / \ /

3 o-C N-C

\\ | w Q R 2 O (wherein A, B, R 1, R 2 and n are as defined above), and in the same way those compounds of formula (I) in which Z represents a group of formula (III) may be represented by formula (Ib):

O

25 U

^ A O-C

\ / \

Pt x! (ib) a N-C-H I I c-ca 30 // \ o ai (where A, B, R 1 and X are as defined above).

In the compounds of the invention, where R 1, R 2, R 3 or R * represents a C 1 -C 4 alkyl group, this may be a straight-chain or branched chain group, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl. In the case of R *, such an alkyl group may be unsubstituted or may have at least one substituent selected from the group consisting of substituents 5 (a), as defined above and described in more detail by way of examples below. In the case of the alkyl groups represented by R 2 and R 7, these may be unsubstituted or may have one or more substituents selected from the group consisting of substituents (c), as defined above and described in more detail by way of examples below.

When R1 represents an alkoxy group, it contains 1 to 4 carbon atoms and may be a straight-chain or branched chain group. Examples of such groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, 15 sec-butoxy and t-butoxy, of which methoxy, ethoxy and propoxy groups are preferred.

When R2 represents an alkyl group, it may be exemplified above in connection with the alkyl groups which R1 may represent, but is preferably a methyl, ethyl, propyl or isopropyl group. Such a group may be substituted or unsubstituted, and when substituted, the substituents are selected from C 1 -C 4 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups as defined and defined above and exemplified below, but most preferably are alkoxyalkyl or alkoxyalkoxy groups. Examples of such substituted groups are methoxymethyl and methoxyethoxymethyl groups (especially 2-methoxyethoxymethyl).

X is a direct carbon-carbon bond or a methylene group.

30

In the compounds of the present invention, when Z represents a group of formula (II), i.e. compounds of formula (Ia), n may be 0 or 1, but is preferably 0, i.e. the compounds are azetidine derivatives.

When the substituent on the C 1 -C 6 alkyl group represented by R is a silyloxy group, it may have 1 to 3, preferably 3 substituents selected from the group consisting of C 1 -C 4 alkyl groups (for example, as in 7 87572 above R 1). described by way of example). Specific examples of such preferred silyloxy groups include dimethyl-t-butylsilyloxy, trimethylsilyloxy, triethylsilyloxy, dimethyl (phenyl) silyloxy, of which dimethyl-t-butylsilyloxy-5 and trimethylsilyloxy groups are preferred.

When the substituent on the C 1 -C 4 alkyl group represented by R 1 is an alkoxy group, it may have 1 to 4 carbon atoms and may be a straight-chain or branched group group. Examples are methoxy, ethoxy, pro-10oxy, isopropoxy, butoxy, sec-butoxy and t-butoxy, of which methoxy, ethoxy and propoxy groups are recommended.

When the substituent on the C 1 -C 4 alkyl group represented by R x is a group of the formula -OPO (OR 3) 2, R 3 may be: an alkyl group as defined above in connection with R 3 and exemplified; or a phenyl group; 20

Most preferably, R3 in this formula represents a methyl, ethyl, propyl or phenyl group.

When the substituent on the C 1 -C 4 alkyl group represented by R x is a group of the formula -O-CO 2 R a, R * may represent: a C 2 -C 9 alkyl group, for example a group methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl , pentyl, isopentyl, hexyl, heptyl, octyl or nonyl, of which C 1 -C 3 groups are more preferred alkyl groups, with C 7 being most preferred;

When the substituents on the C 1 -C 4 alkyl group represented by R 2 represent an alkoxy group, it may be as defined above in connection with R * and described by way of example. When a substituent denotes an alkoxy-sialkoxy group, it may be as defined and exemplified above in connection with the C 1 -C 6 alkyl group of the substituents R *.

8 87572

Examples of preferred compounds which A and / or B may represent are ammonia, isopropylamine, ethylenediamine, trimethylenediamine, 2-methyltetramethylenediamine, 2,2-diethylpropylene-1,3-diamine, 1,2-diaminocyclohexane, 1, 2-diaminocycloheptane, 1,3-diaminocyclooctane, 1-amino-2-aminomethylcyclohexane, 1,1-bis (aminomethyl) cyclohexane, 5,5-bis (aminomethyl) -1,3-dioxane, 2-aminomethylpyrrolidine and 2-aminomethylpyridine.

Examples of preferred groups that R 1 may represent are methyl, ethyl, isopropyl, phenyl, benzyl, methoxymethyl, 1-hydroxyethyl, 1-trimethylsilyloxyethyl, 1- (t-butyldimethylsilyloxy) ethyl, 1- (dimethylphosphonooxy) ethyl, 1- (diethylphosphonoxy) ethyl, 1- (diphenylphosphonooxy) ethyl, 1-methoxyethyl, 1-methoxymethoxyethyl, 1- (2-methoxyethoxymethoxy) ethyl, 1- (ethoxymethoxy) ethyl, 1-acetoxyethyl, 1 -propionyloxyethyl, 1-butyryloxyethyl, 1-valeryloxyethyl, 1-hexanoyloxyethyl, 1-heptanoyloxyethyl, 1-octanoyloxyethyl, 1-nonaoyloxyethyl, 1- (methoxyacetoxy) ethyl, 1- (phenoxyacetoxy) ethyl, phenylacetoxy) ethyl, 1- (3-phenylpropionyloxy) ethyl, 1- (2-thienylacetoxy) -20 ethyl, 1- (2-furylacetoxy) ethyl, 1-methanesulfonyloxyethyl, 1-ethanesulfonyloxyethyl, 1-benzenesulfonyloxyethyl and methoxy.

Examples of preferred groups that R 2 may represent are methyl, ethyl, isopropyl and methoxymethyl.

Examples of preferred classes of compounds of the present invention are as follows: (A) Compounds of formula (Ia) wherein n is 0.

(B) Compounds of formula (I) wherein: A and B are independently selected from the group consisting of amine groups; or 9 87572 A and B together represent diamino-C 3-8 cycloalkyl groups, wherein said alicyclic compound has two substituents selected from the group consisting of amino groups and C 1 -C 6 aminoalkyl-5 groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from a group comprising amino groups and C 1 -C 18 aminoalkyl groups; and Z represents a group of formula (II): 10 // -C (CH2) n 1 W \ c ch-r1 an \ / \ / 111 'Ο-c H_c 15 W | \\ a22 or a group of formula (III): 20 0 //

O-C

/ \ \ / x (: II> N-C-h

·· 25 I I

C-CH

• il \

O

Wherein: R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a substituted C 1 -C 4 alkyl group having at least one substituent selected from the group consisting of substituents (a),

R 2 represents a hydrogen atom, a C 1 -C 4 alkyl group, a substituted C 1 -C 1 alkyl group having at least one substituent selected from the group consisting of substituents (c), X represents a single carbon a carbon bond or a methylene group; 5 n is 0 or 1; the substituents fa) are selected from the group consisting of hydroxy groups, silyloxy groups having 1 to 3 C 1 -C 4 alkyl substituents on silicon, C 1 -C 4 alkoxy groups, groups of the formula -OPO (OR 3) 2 and -O- 10 COR * and C2-C5 alkoxyalkoxy groups; wherein: R3 represents a C1-C4 alkyl group or a phenyl group, R * represents a C1-6 alkyl group, the substituents (c) are selected from the group consisting of C1-C4 alkoxy groups and C2-C5 alkoxyalkoxy groups; (C) Compounds as in (B) when n is 0.

(D) Compounds of formula (Ia) when: A and B are independently selected from the group consisting of amine groups; or A and B together represent a group which is a diamino-C 3-8 cycloalkyl group, wherein said alicyclic compound has two substituents selected from the group consisting of amino groups and C 1 -C 2 aminoalkyl groups, and wherein said nitrogen-containing heterocyclic compound has one a substituent selected from the group consisting of amino groups and C1-C2 aminoalkyl groups; U 87572 R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a substituted C 1 -C 4 alkyl group having at least one substituent selected from the group consisting of substituents (a '), R 2 represents a hydrogen atom, a C 1 -C 4 alkyl group , having at least one substituent selected from the group consisting of substituents (c '); the substituents (a ') are selected from the group consisting of hydroxy groups, silyloxy groups having 1 to 3 C 1 -C 6 alkyl substituents in silicon-10 wherein, C 1 -C 3 alkoxy groups and groups of the formula -OPO (OR 3) 2, and -O-COR 4; wherein: R 3 represents a C 1 -C 6 alkyl group or a phenyl group, R * represents a C 1 -C 6 alkyl group, the substituents (c ') are selected from the group consisting of, C 1 -C 3, alkoxy groups and C 2 -C 5 - Alkoxyalkoxy; (E) Compounds as in (D) when n is 0.

(F) Compounds of formula (Ia) when: A and B are independently selected from the group consisting of amine groups; or • - A and B together denote a compound which is a diamino-C 3-9 cycloalkyl group, wherein nia I n i I 11. r:. · i a I 1 cyc 1 I s compound has two melt. · ;! selected from the group consisting of amino groups and C1-C2-aminoalkyl groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from the group consisting of i2 87572 f. ', -C2- <' iininoal kyyl iryhinät; R1 means: a hydrogen atom; C ^ C ^ alkyl group; a substituted alkyl group having at least one substituent selected from the group consisting of C 1 -C 3 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups and silyloxy groups having 3 C 1 -C 3 alkyl substituents on a silicon atom; R 2 represents a hydrogen atom, a C 1 -C 2 alkyl group or a substituted C 1 -C 2 alkyl group having at least one substituent selected from the group consisting of C 1 -C 2 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups; and n is 0.

(G) Compounds of formula (Ia) when: Λ and B are independently selected from the group consisting of amine groups; or A and B together represent a compound which is a diamino-C 3-9 cycloalkyl group, said alicyclic compound having two substituents selected from the group consisting of amino groups and aminomethyl groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from the group consisting of aminomethyl groups; R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a substituted C 1 -C 3 alkyl group having at least one substituent selected from the group consisting of C 1 -C 2 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups and silyloxy groups having 3 C 1 -C 4 alkyl substituents on the silicon atom; R 2 represents a hydrogen atom, a (C 1-6 alkyl group or a substituted C 1 -C 2 alkyl group having at least one substituent selected from the group consisting of C 1 -C 4 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups; and

Sr? Γ "r ·? R 'Ιϊΐι η is 0, (H) Compounds of formula (Ib) when: 5 A and B are independently selected from the group consisting of amine groups; or 10 A and B together represent a compound , which is a diamino-C3A cycloalkyl group, wherein said alicyclic compound has two substituents selected from the group consisting of amino groups and C1-C2 aminoalkyl groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from the group consisting of amino groups, and C 1 -C 2 aminoalkyl groups, R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a substituted C 1 -C 4 alkyl group having at least one substituent selected from the group consisting of substituents (a "); the substituents (a ") are selected from the group consisting of hydroxy groups, silyloxy groups having 1 to 3 C 1 -C 6 alkyl substituents in silicon-25, C 1 -C 6 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups, C 3 -C 7 alkoxyalkoxyalkoxy groups groups of the formula -OPO (OR 3) 2 and -O-COR 4, wherein: R 3 represents a C 1 -C 4 alkyl group or a phenyl group, R 4 represents a C 1 -C 8 alkyl group, (I) Compounds of formula (Ib) , when: A and B are independently selected from the group consisting of amine groups, or A and B together represent a compound which is a diamino-C 3-8 cycloalkyl group, said alicyclic compound having two substituents selected from the group consisting of amino groups and C 1 -C 2 aminoalkyl groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from the group consisting of C 1 -C 2 aminoalkyl groups; R 1 represents a hydrogen atom, (C 1 -C 4 alkyl group) , Cx-C4 alkoxy group, a substituted C1-C4 alkyl group which has one substituent selected from the group consisting of substituents (a '' '); The substituents (α''1 ') are selected from the group consisting of silyloxy groups having 3 C 1 -C 4 alkyl substituents on the silicon atom and C 1 -C 6 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups, C 3 -C 7 alkoxyalkoxyalkoxy groups and groups of the formula -OPO (OR3) 2 and -O-COR4; With 20 objects: R3 represents a C1-C8-alkyl group or a phenyl group, and R4 represents a C1-C8-alkyl group; (J) Compounds of formula (Ib) wherein: A and B are independently selected from the group consisting of amine groups; or A and B together represent a diamino-C 3-8 cycloalkyl group, wherein said alicyclic compound has two substituents selected from the group consisting of amino groups and C 1 -C 2 aminoalkyl groups, and wherein said nitrogen-containing heterocyclic compound has one substituent selected from the group consisting of C1-C2 aminoalkyl groups; R 1 represents a hydrogen atom, a C 1 -C 2 alkyl group, a C 1 -C 2 alkoxy group, a substituted C 1 -C 4 alkyl group having at least one substituent selected from the group consisting of substituents (aiv) or a halogen atom; The substituents (atv) are selected from the group consisting of silyloxy groups having 3 C 1 -C 5 alkyl substituents on a silicon atom, C 1 -C 3 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups, C 3 -C 7 alkoxyalkoxyalkoxy groups and groups of the formula -OPO (OR3) 2 and -O-COR *; Wherein: R 3 represents a C 1 -C 4 alkyl group or a phenyl group, and R a represents a C 1 -C 6 alkyl group.

20

When reference is generally made above to "substituted" groups, there is no limitation on the number of substituents other than those caused by the number of substitutable positions and / or steric packages, as is well known to those skilled in the art.

However, in most cases no more than 3 substituents are expected (although this is also mentioned for convenience only and is in no way related to the essence of the invention) and normally only one substituent is recommended in this case, unless otherwise indicated.

30

The compounds of the present invention may exist in the form of various geometric isomers with respect to the platinum atom and possibly due to the asymmetric carbon atoms of the groups in the compounds. The present invention encompasses both private isolated isomers and mixtures thereof. Individual isomers may be prepared by stereo-specific synthetic techniques or may be prepared by separation of mixtures of isomers, as is well known in the art. There is also P 7 7 7 9 16 '->! Hyvin l l It is well known that some isomers may be more active than others, and this can be readily determined for any pair of isomers using standard laboratory techniques.

Examples of specific compounds of the invention are given in the following formulas (1-1) to (1-5), wherein the substituents are as defined in the corresponding Tables 1-5 [i.e., Table 1 relates to formula (1-1, Table 2 relates to formula (1- 2) etc.] The following abbreviations are used in the tables: 10

Ac acetyl

Bes benzenesulfonyl tBu t-butyl

Byr butyryl 15 Bz benzyl

You are not ethyl or ethylene, depending on the context

Hpo heptanoyl cHx cyclohexyl

Hxo hexanoyl 20 Me methyl or methylene, depending on the context

Mes methanesulfonyl cOc cyclooctyl

Octo octanoyl

Ph phenyl 25 Pr propyl iPr isopropyl

Prn propionyl. Pyrdyrrolidinyl: ‘Va valeryl 30

In Tables 4 and 5, in the column for X, the dash (-) indicates a direct bond.

r, 17 87572 / ° / —c 'α2 Μ \ / v_y \ —ci

C-CH

/ ^ - / ^ ΝΗ2 '/ \ -C-R7 11-51

I I

C-CH

ie 87572

O

i1 Λ- {/ ICH2ln \

N / V W (I-1I

/ - (\ - (• il · o ^ / 0 - </ <CH2ln \ w '· L 1, 1, / \ / \ / \ / ”-31

A, X H-CU

C-CH

// V, o *

Table 1 i9 b / b / 2

Compound n A1 R1 R2 No. 5 _ 1-1 o h3n h h

1-2 0 H3N Me H

1-3 0 H3N H Me 1-4 0 H3N Me Me 10 1-5 0 H3N H MeOMe 1-6 0 H3N H 2 -MeOEtOMe

1-9 0 H3N iPr H

1-10 0 H3N iPr Me 1-11 0 H3N iPr MeOMe

15 1-12 0 H3N MeOMe H

1-14 0 H3N 1-MeOEt H

1-15 0 H3N 1-MeOEt Me 1-16 0 H3N 1-MeOEt MeOMe

1-17 1 H3N H H

20 1-19 0 iPrNH2 H H

1-20 0 iPrNH2 Me H

1-21 0 iPrNH2 H Me 1-22 0 iPrNH2 Me Me 1-23 0 iPrNH2 H MeOMe 25 1-24 0 iPrNH2 H 2-MeOEtOMe

•: 1-27 0 iPrNH2 iPr H

1-28 0 iPrNH2 iPr Me 1-29 0 iPrNH2 iPr MeOMe

1-30 0 iPrNH2 MeOMe H

30 1-32 0 iPrNH2 1-MeOEt H

1-33 0 iPrNH2 1-MeOEt Me 1-34 0 iPrNH2 1-MeOEt MeOMe

1-35 1 iPrNH2 H H

1-36 1 iPrNH2 H H

35 _______

Compound n R1 R2 Az 5 No. 20 8 7 5 7 2

Table 2 2-19 0 HH 1,2-diNHzcHx 2-20 0 Me H 1 ^ -diNH ^ Hx 2-21 OH Me 1,2-diNHzcHx 10 2-22 0 Me Me 1,2-diNHzcHx 2-23 0 H MeOMe 1,2-diNHzcHx 2-24 0 H 2-MeNEcOMx 1,2-diNHzcHx 2-27 0 iPr H 1,2-diNHzcHx 2-28 0 iPr Me l, 2-diNHzcHx 15 2-29 0 iPr MeOMe 1.2 -diNHzcHx 2-30 0 MeOMe H 1,2-diNHzcHx 2-32 0 1-MeOEt H 1,2-diNHzcHx 2-33 0 1-MeOEt Me 1,2-diNHzcHx 2-34 0 1-MeOEt MeOMe 1, 2 -diNHzcHx 20 2-35 1 HH 1,2-Cl i NilzcHx 2-73 OH H 1,3-diNHz-2,2-diEtPt 2-74 0 Me H 1,3-diNHz-2,2-diEtPt 2- 75 OH Me 1,3-diNH 2 -2-diEtPt '2-76 0 Me Me 1,3-diNH 2 -2-diEtPt; / 25 2-77 0 H MeOMe 1,3-diNHz-2,2-diEtPt 2-78 0 H 2-MeOEtOMe 1,3-diNHz-2,2-diEtPt: 2-81 0 iPr H 1,3-diNHz -2,2-diEtPt 2-82 0 iPr Me 1,3-diNHz-2,2-diEtPt 2-83 0 iPr MeOMe 1,3-diNHz-2,2-diEtPt 30 2-84 0 MeOMe H 1.3 -diNHz-2,2 - diEtPt 2-86 0 1-MeOEt H 1,3-diNHz-2,2-diEtPt 2-87 0 1 -MeOEt Μι · 1,3 - dl NHZ-2,2-di Et Pt 2-88 0 1-MeOEl MeOMe 1,3-dLNHz-2,2-diEtPl 2-89 1HH 1,3-diNHz-2,2-diEtPt 35 2-91 OH H 1,2-diNHzcOc 2-92 0 Me H 1,2-diNH 2 O 2 2-93 0 H Me 1,2-diNH 2 Oc: 2-94 0 Me Me 1,2-diNH 2 OO

Compound n R1 Rz A2 5 No. 2i 87572

Table 2 (continued) 2-95 0 H MeOMe 1,2-diNH 2 Oc 2-96 0 H 2-MeOEtOMe 1,2-diNH 2 Oc 2-99 0 iPr H 1, 2-diNH 2 Oc 10 2-100 0 iPr Me l ^ - diNHgcOc 2-101 0 iPr MeOMe 1,2-diNH2cOc 2-102 0 MeOMe H 1,2-diNHzcOc 2-104 0 1-MeOEt H 1,2-diNH2cOc 2-105 0 1-MeOEt Me 1,2-diNH2cOc 15 2-106 0 1-MeOEt MeOMe 1,2-diNH 2 OOc 2-10 / 11 11 II 1,2-diNII2 (-O <'

Table 3

Compound X A1 R1 5 No., r rr λ 22 b / Ό / Z, 3-1 - H3N 1-HOEt 3-2 - H3N 1- (OSiMe3) Et 3-3 - H3N1- (0SiMe2tBu) Et 10 3-4 - H3N 1- [OPO (OEt) 2] Et 3-5 - H3N 1- [OPO (OPh) 2] Et 3-6 - H3N 1-AcOEt 3-7 - H3N 1-PrnOEt 3-8 - H3N 1-ByrOEt 15 3-9 - H3N 1-VaOEt 3-10 - H3N 1-HxoOEt 3-11 - H3N 1-HpoOEt 3-12 - H3N 1- (OctoO) Et 3-14 - H3N 1- (MeOAcO) Et 2 O 3-15 - H3N 1- (PhOAcO) Et 3-16 - H3N 1- (PhAcO) Et 3-17 - H3N 1-MeOEt 3-18 - H3N 1- (MeOMeO) Et 3-19 - H3N 1- [MeOEtOMeO] Et 25 3-21 - H3N 1-BesOEt - - 3-22 CH2 iPrNH2 1-HOEt. · 3-23 CH2 iPrNH2 1- (OSiMe3) Et. · 3-24 CI12 iPrNll2 1- (0SiMo2tBu) Et. 3-25 (; ll2 iPrNH2 1- [OPO (OEt) 2] Et 30 3-26 CH2 iPrNH2 1- [OPO (OPh) 2] Et 3-27 CH2 iPrNH2 1-AcOEt 3-28 CH2 iPrNH2 1-PrnOEt 3 -29 CH2 iPrNH2 1-ByrOEt 3-30 CH2 iPrNH2 1-VaOEt. ·· 35 3-31 CH2 iPrNH2 1-HxoOEt 3-32 CH2 iPrNH2 1-HpoOEt 3-33 CH2 iPrNH2 1- (OctoO) Et 3-35 CH2 iPrNH2 1- (MeOAcO) Et

Compound X A1 R1 5 no

Table 3 (continued) r. 23 r π o 23 6 / s / / 3-36 CH2 iPrNH2 1- (PhOAcO) Et 3-37 CH2 iPrNH2 1- (PhAcO) Et 3-38 CH2 iPrNH2 1-MeOEt 10 3-39 CH2 iPrNH2 1- (MeOMeO ) Et 3-40 CH2 iPrNH2 1- [MeOEtOMeO] Et 3-42 CH2 iPrNH2 1-BesOEt 3-43 CH2 H3N 1-HOEt 3-44 CH2 H3N 1- (OSiMe3) Et 15 3-45 CH2 H3N 1- (OSiMe2tBu ) Et 3-46 CH2 H3N 1- [OPO (OEt) 2] Et 3-47 CH2 H3N 1- [0P0 (0Ph) 2] Et 3-48 CH2 H3N 1-AcOEt 3-49 CH2 H3N 1-PrnOEt 20 3 -50 CH2 H3N 1-ByrOEt 3-51 CH2 H3N 1-VaOEt 3-52 CH2 H3N 1-HxoOEt 3-53 CH2 H3N 1-HpoOEt '3-54 CH2 H3N 1- (OctoO) Et 25 3-56 CH2 H3N l - (MeOAcO) Et 3-57 CH2 H3N 1- (PhOAcO) Et. . · 3-58 CH2 H3N 1- (PhAcO) Et 3-59 CH2 H3N 1-MeOEt 3-60 CH2 H3N 1- (MeOMeO) Et 30 3-61 CH2 H3N 1- [MeOEtOMeO] Et 3-63 CH2 H3N 1- BesOEt 24 * 7572

Table 4

Compound X R1 A2 5 No. 4-43 - 1-HOEt 1,2-diNH2cHx 4-44 - 1- (OSiME3) Et 1,2-diNH2cHx 4-45-1- (0SiME2tBu) Et 1,2-diNH2cHx 4-46-1- [0PO (0Et) 2] Et 1,2-diNH2cHx 4-47-1- [0PO (0Ph) 2] Et 1,2-diNH2cHx 4-48-1-AcOEt 1,2- diNH2cHx 4-49 - 1-PrnOEt 1,2-diNHzcHx 4-50 - 1-ByrOEt 1,2-diNH2cHx 15 4-51 - 1-VaOEt 1,2-diNH2cHx 4-52 - 1-HxoOEt 1,2-diNH2cHx 4-53 - 1-HpoOEt 1,2-diNH2cHx 4-54 - 1- (OctoO) Et 1,2-diNH2cHx 4-56 - 1- (MeOAcO) Et 1,2-diNH2cHx20 4-57 - 1- ( PhAcO) Et 1,2-diNH 2 CHx 4-58-1- (PhAcO) Et 1,2-diNH 2 cHx 4-59-1-MeOEt 1-diNH 2 Hx 4-60-1- (MeOMeO) Et 1,2- diNH2cHx '' 4-61 - 1- [MeOEtOMeO] Et 1,2-diNH2cHx •: 25 4-63 - 1-BesOEt 1,2-diNH2cHx 4-64 CH2 1-HOEt 1,2-diNH2cHx ·. : 4-65 CH2 1- (OsIMe3) Et 1,2-diNH2cHx 4-66 CH2 1- (OSiME2tBu) Et 1,2-diNH2cHx 4-67 CH2 1- [OPO (OEt) 2] Et 1,2-diNH2cHx 30 4-68 CH2 1- [OPO (OPh) z] Et 1,2-diNH2cHx 4-69 CH2 1-AcOEt 1,2-diNH2cHx 4-70 CH2 1-PrnOEt 1,2-diNH2cHx 4-71 CH2 1- ByrOEt 1,2-diNH2cHx 4-72 CH2 1-VaOEt 1,2-diNH2cHx 35 4-73 CH2 1-HxoOEt 1 ^ -diNHaCHx 4-74 CH2 1-HpoOEt 1 ^ -diNH ^ Hx 4-75 CH2 1- ( OctoO) Et 1,2-diNHzcHx 4-77 CH2 1- (MeOAcO) Et 1,2-diNHzcHx 25 8 7 5 7 2

Table 4 (continued)

Compound X R 1 A2 5 No. 4-78 CH 2 1- (PhOAcO) Et 1 H -diNH 2 Hx 4-79 CH 2 1- (PhACo) Et 1,2-diNHacHx 4-80 CH 2 1 -MeOEt 1 H -DiNH 2 Hx 10 4-81 CH2 1- (MeOMeO) Et1-diNH2Hx 4-82 CH2 1- [MeOEtOMeO] Et 1,2-diNH2cHx 4-83 CH2 1-MesOEt 1,2-diNH2cHx 4-84 CH2 1- BesOEt 1 ^ -diNH ^ Hx 4-85 - 1-HOEt 1-NH2 - 2 - NH2MecHx 15 4-86 - 1- (0SiME3) Et 1 -NH2-2-NH2MecHx 4-87 - 1- (0SiMe2tBu) Et 1 -NH2-2-NH2MecHx 4-88 - 1- [OPO (OEt) 2] Et 1-NH2-2-NH2MecHx 4-89 - 1- [OPO (OPh) 2] Et 1-NH2-2-NH2MecHx 4- 90 - 1-AcOEt 1-NH2-2 -NH2MecHx 20 4-91 - 1-PrnOEt 1-NH2-2 -NH2MecHx 4-92 - 1-ByrOEt 1-NH2-2 -NH2MecHx 4-93 - 1-VaOEt 1- NH2-2-NH2MecHx 4-94 - 1-HxoOEt 1-NH2-2 -NH2MecHx: 4-95 - 1-HpoOEt 1 - NH2 - 2 - NH2MecHx 25 4-96 - 1- (OctoO) Et 1 -NH2-2 -NH2MecHx ... '4-98 - 1- (MeOAcO) Et1 -NH2-2-NH2MecHx 4-99-1- (PhOAcO) Et1-NH2-2-NH2MecHx 4-100-1- (PhAcO) Et 1 -NH2-2-NH2MecHx 4-101 - 1-MeOEt 1-NH2-2-NH2MecHx 30 4-102 - 1- (MeOMeO) Et 1-NH2-2-NH2MecHx 4-103 - 1- [MeOEtOMeOJEt 1-NH2 -2-NH2MecHx 4-105 - 1-BesOEt 1-NH2-2-NH2MecHx 4-106 CH2 1-HOEt 1-NH 2- 2 -NH2MecHx 4-107 CH2 1- (OSiME3) Et 1-NH2-2-NH2MecHx 35 4-108 CH2 1- (0SiMe2tBu) Et 1-NH2-2-NH2MecHx 4-109 CH2 1- [OPO (OEt ) 2] Et 1-NH2-2-NH2MecHx 4-110 CH2 1- [0PO (0Ph) 2] Et 1-NH2-2 -NH2MecHx 4-111 CH2 1-AcOEt 1 - NH2 - 2 - NH2MecHx 7r π 0 7 1

Table 4 (continued)

Compound X R1 A2 5 No. 4-112 CH2 1-PrnOEt 1-NH2-2-NH2MecHx 4-113 CH2 1-ByrOEt 1-NH2-2-NH2MecHx 4-114 CH2 1-VaOEt 1 - NH2 - 2 - NH2MecHx 10 4-115 CH2 1-HxoOEt 1-NHZ-2 -NH2MecHx 4-116 CH2 1-HpoOEt 1-NH2-2-NH2MecHx 4-117 CH2 1- (OctoO) Et 1-NH2-2-NH2MecHx 4-119 CH2 1- (MeOAcO) Et 1 NH2-2 -NH2MecHx 4-120 CH2 1- (PhOAcO) Et 1-NH2-2-NH2MecHx 15 4-121 CH2 1- (PhAcO) Et 1-NH2-2-NH2MecHx 4- 122 CH2 1-MeOEt 1-NH2-2 -NH2MecHx 4-123 CH2 1- (MeOMeO) Et 1 -NH2-2-NH2MecHx 4-124 CH2 1- [MeOEtOMeO] Et 1-NH2-2-NH2MecHx 4-126 CH2 1 -BesOEt 1-NH2-2-NH2MecHx 20 4-169 - 1-HOEt 1,2-diNH2cOc 4-170 - 1- (OSiMe3) Et 1,2-diNH2cOc 4-171 - 1- (OSiMe2tBu) Et 1, 2-diNH 2 Oc 4-172-1- [OPO (OEt) 2] Et 1 H -diNH 2 Oc 4-173-1- [OPO (OPh) 2] Et 1 H -diNH 2 Oc 25 4-174 - 1-AcOEt 1 ^ -diNHjcOc 4-175 - 1-PrnOEt 1,2-diNH2cOc 4-176 - 1-ByrOEt 1 ^ -diNHjcOc. : 4-177 - 1-VaOEt 1,2-diNH2cOc 4-178 - 1-HxoOEt 1,2-diNH2cOc: 30 4-179 - 1-HpoOEt 1,2-diNH2cOc 4-180 - 1- (OctoO) Et 1,2-diNH2cOc 4-182-1- (MeOAcO) Et1 ^ -diNH ^ Oc • '4-183-1- (PhOAcO) Et1 ^ -diNH ^ Oc 4-184-1- (PhAcO) Et 1,2-diNH2cOc 35 4-185 - 1-MeOEt 1 ^ -diNHjcOc 4-186 - 1- (MeOMeO) Et 1 ^ -diNH ^ Oc 4-187 - 1- [MeOEtOMeO] Et 1,2-diNH2cOc 4-189 - Ι-BesOEt 1,2-diNH2cOc

Compound X R1 A2 5 No. 27 b 7 5 7 2

Table 4 (cont'd) 4-190 CH2 1-HOEt 1,2-diNH2cocc 4-191 CH2 1- (0SiMe3) Et1 ^ -diN ^ Oc 4-192 CH2 1- (OSiMe ^ BuJEt l ^ -diNH ^ Oc 10 4-193 CH2 1- [OPO (OEt) 2] Et 1,2-diNH2cOc 4-194 CH2 1- [OPO (OPh) 2] Et 1,2 -diNH2 Oc4-195 CH2 1-AcOEt 1,2- diNH2cOc 4-196 CH2 1-PrnOEt 1,2-diNH2cOc 4-197 CH2 1-ByrOEt 1,2-diNH2cOc 15 4-198 CH2 1-VaOEt 1,2-diNH2cOc 4-199 CH2 1-HxoOEt 1,2-diNH2c 4-200 CH2 1-HpoOEt 1,2-diNH2cOc 4-201 CH2- (OctoO) Et 1,2-diNH2cOc 4-203 CH2 1- (MeOAcO) Et 1,2-diNH2cOc 20 4-204 CH2 1- (PhOAcO) Et 1,2-diNH 2cOc 4-205 CH 2 1- (PhAcO) Et 1,2-diNH 2cOc 4-206 CH 2 1-MeOEt 1-diNH 2 Oc 4-207 CH 2 1- (MeOMeO) Et 1 - DiNH ^ Oc 4-208 CH2 1- [MeOEtOMeO] Et 1 ^ -diNHjcOc 25 4-210 CH2 1-BesOEt 1 ^ -diNHacOc

Compound X R 1 R 7 5 no

Table 5 28 8 7 5 7 2

5-1 - H H

5-2 - Me H

5-3 - MeO H

10 5-9 CHZ H H

5-10 CH2 Me H

5-11 CH2 MeO H

Of the compounds listed above, the most preferred are: 1,2-diaminocyclohexaneplatinum (II) 2-oxoazetidine-4,4-dicarboxylate, especially cis-f trans- (E) -1,2-diaminocyclohexane platinum (II) 2-oxoazetidine-4 , 4-dicarboxylate-isomer; 1,2-Diaminocyclohexane platinum (II) (1-methyl-2-oxoazetidine-4,4-dicarboxylate), especially cis- [trans- (i) -1,2-diaminocyclohexane] platinum (II) (1-methyl- 2-oxoacetidine-4,4-dicarboxylate) isomer; 1,2-Diaminocyclohexaneplatinum (II) (1-methoxymethyl-2-oxoacetyl-____; didine-4,4-dicarboxylate), especially cis-trans ((1) -1,2-diaminocyclohexane) platinum (II) (1 -methoxymethyl-2-oxoazetidine-4,4-dicarboxylate) isomer; 1,2-Diaminocyclohexaneplatinum (II) [1- (2-methoxyethoxy) methyl-2-oxoazetidine-4,4-dicarboxylate], especially cis-trans- (E) -1,2-diaminocyclohexane] platinum (II) [1- ( 2-metoksletoksi) methyl-2-oxoazetidine-4,4-dicarboxylate] isomer; 35 1,2-Diaminocyclohexaneplatinum (II) (1-methyl-3-isopropyl-2-oxoazetidine -4,4-dicarboxylate), especially cis-trans (1) -1,2-diaminocyclohexane] platinum (II) (1-methyl- 3-isopropyl-2-oxoacetate (87,472,522 thidine-4,4-dicarboxylate) isomer; 1,2-diaminocyclohexaneplatinum (II) 3- [1- (methoxymethoxy) ethyl] -2-oxoazetidin-4-ylacetate, especially cis-trans ((1) -1,2-diaminocyclohexane] platinum (II) ((3S, 4R) -3 - [(R) -1- (methoxymethoxy) ethyl] -2-oxoazetidin-4-yl) acetate isomer; 1,2-diaminocyclohexaneplatinum (II) 3- [1- (2-methoxyethoxymethoxy) ethyl] -2-oxoazetidin-4-ylacetate, especially cis-trans - (E) -1,2-diaminocyclohexane] platinum (II) 1 (3S, 4R) -3 - [(R) -1- (2-methoxy-ethoxymethoxy) -ethyl] -2-oxo-azetidin-4-yl} -acetate isomer; 1,2-diaminocyclohexaneplatinum (II) 3- [1- (octanoyloxyethyl) -2-oxoazetidin-4-ylcarboxylate, especially cis-trans - (1) -1,2-15 diaminocyclohexane] platinum (II) {(3S, 4S) -3 - [(R) -1-Octanoyloxy-ethyl] -2-oxo-azetidin-4-ylcarboxylate isomer; and 1,2-diaminocyclohexane platinum (II) 3- (1-t-butyldimethylsilyloxyethyl) -2-oxoazetidin-4-ylcarboxylate, especially cis- [trans- (1) -1,2-diaminocyclohexane] platinum (II) {(3S, 4S) -3 - [(R) -1-t-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-ylcarboxylate isomer.

The compounds of the present invention can be prepared by a variety of methods well known in the art of preparing these types of complexes. Examples of suitable preparation procedures are illustrated in the following reaction schemes: 3o S7572 R e a k 11 o k a a ν ί ο Λ 1

A Mh \ / COOM

X + J-XcOOM

B7 X0H02 o \ „2

(VI (VII

0 A, / 0 C. / 'CH2'n \

__ \ / \ 7 CH-R1 (I and I

g / \ - ^ ^^ 8 \ I -v.

0 1.2 0

Reaction Scheme A 2

\ y0MO2 _f X — COOH

XPt +

/ \ J-MH

87 X0K02 0 / (YU |

(VI

/ \ / \ -— pt / *

S'7 "\ -CH-R7 {lb I

I I

C-CH

In V

3i 87572; R e a k tLocal diagram B l

R1 (CH2) n COOH

‘X J’, Y V

/ P, \ J-N XC00H

8 OH (Y \ r2 (VI !!] (IX) - ~ (la) R reaction scheme B?, ,, Ί. — y <- <··> ^ +>

/ \ J-NH

0 OH

<V1II> (VII) - (lb) 32 87572

In the above formulas, A, B, R 1, R 2, R 7, X and n are as defined above and R 7 is a hydrogen atom. M represents an atom of a metal capable of providing an alkaline reaction medium, especially sodium or potassium.

The platinum complexes of formulas (V) and (VIII) used as starting materials are well known compounds. The mono- and dicarboxylic acids of the formulas (VII) and (IX) and the salt of the formula (VI) can be prepared as described in Japanese Patent Application No. 56-142259.

10

In Reaction Scheme A1, a compound of formula (V) is reacted with a compound of formula (VI) to give the desired compound of formula (Ia). This reaction is preferably carried out by adding a salt of formula (VI), preferably an equivalent amount or a small molar excess to the complex of formula (V), preferably in an alkaline solution or aqueous suspension. In Reaction Scheme A2, a compound of formula (V) is reacted with a compound of formula (VII) to give the desired compound of formula (Ib). This reaction is preferably carried out by adding an equivalent or a slight molar excess of the acid of formula (VI) and an amount corresponding to about two equivalents of alkali (e.g. alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or alkaline resin) to the complex of formula (V), preferably in aqueous solution or suspension in water. Alternatively, the process of Reaction Scheme A1 can be carried out using an acid corresponding to a salt of formula (VI) in such an initial manner. In the presence of 25 I or the process of Reaction Scheme 2, ____; using a salt corresponding to the acid of formula (VII) without the addition of the claimed. . without any alkali.

Both reactions are carried out at a temperature of 0 to 50 ° C, although the reaction temperature is not very critical to the present invention. The time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the quality of the reagents, but normally between 20 minutes and 5 days is sufficient for Reaction Scheme A1 and between 20 minutes and 20 days is sufficient for the reaction of Reaction Scheme A2.

When the reaction is found to be complete, the resulting precipitate can usually be collected by filtration. However, if the desired compound does not precipitate as crystals, the compound can be recovered by the following reaction sequences: first, the reaction mixture is concentrated by evaporation under reduced pressure; the residue is mixed with a solvent which does not adversely affect the desired compound; this can cause the desired compound to crystallize - if this happens it can be collected by filtration; alternatively, the resulting solution may be purified by any of a variety of chromatographic techniques, such as column chromatography, e.g., using an adsorbent resin such as Diaion (trademark) CHP-20P or 10 Sephadex (trademark), or an ion exchange resin to give the desired compound i.

The starting complex of formula (VIII) used in Reaction Schemes B1 and B2 can be prepared by treating the complex of formula (V) with an alkali (e.g., an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide) or an alkaline resin). This can then be reacted with a compound of formula (IX) or (VII) in the same manner as described for Reaction Schemes A1 and A2.

The compounds of the present invention have shown excellent antitumor activity comparable to or superior to that of cisplatin or carboplatin. In addition, it has been found, quite unexpectedly, that the compounds of the present invention are just as effective against cisplatin-resistant murine leukemia L1210. In addition, the compounds of the invention appear to have a surprisingly limited number of side effects, such as nephrotoxicity and bone marrow loss, and have a very high solubility * 'in water, which makes them very easy to ingest. Tumor species against which the compounds have been tested are considered to provide a model estimate of 30 given the probable value of the compound in the treatment of tumors affecting humans.

There is no particular restriction on the mode of administration, but when used as a carcinostatic agent, the compounds of the present invention are preferably administered parenterally, for example, by injection. The dosage may vary depending on the age, body weight and condition of the patient as well as the nature and severity of the tumor, but it is generally recommended that the compound be dosed from 10 mg to several grams per day in adult patients, usually in divided doses.

The invention is further described with reference to the following non-limiting examples. The preparation of certain starting materials used in these examples is then described in Preparations. The forthcoming Experiment describes the biological activity of certain compounds of the present invention.

EXAMPLE 1 cis-trans- (E) -1,2-Diaminocyclohexane-1-platinum (II) 2-oxoazetidine-4,4-dicarboxylate 15 g of cis-trans- (1) -1,2-diaminocyclohexanylplatinum (II) dinitrate were suspended in 80 to 1 ml of water and the suspension was stirred at 28 ° C overnight. After this time, the reaction mixture was concentrated by evaporation under reduced pressure to a volume of about 45 ml, and then 1 g of sodium 2-oxoazetidine-4,4-dicarboxylate (prepared as described in Preparation 1) was added to the concentrate. The mixture was then adjusted to pH 6.1 by the addition of aqueous sodium hydroxide solution and stirred for about 2 hours while cooling with ice. The precipitated crystals were collected - by filtration and washed with small amounts of water and diethyl ether to give 0.58 g of the title compound.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.1 (4H, multiplet); 1.3-1.45 (2H, doublet); Δ 1.8-1.9 (2H, doublet-like); 2.1-2.3 (2H, multiplet); V 3.74 (2H, singlet).

EXAMPLE 2 cis-Diammine platinum (II) 2-oxoazetidine-4,4-dicarboxylate 5 Solution containing 200 mg of sodium 2-oxoazetidine-4,4-dicarboxylate (prepared as described in Preparation 1) 5 in 1 ml of water was added to a suspension of 347 mg of cis-diamine (Latin) di-nitrate in 5 ml of water, and the mixture was stirred at room temperature overnight. After this time, the precipitated crystals were collected by filtration and washed with small amounts of water and diethyl ether to give 219 mg of the title compound, which was further purified by recrystallization from water.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 3.76 (2H, singlet).

EXAMPLE 3 cis-trans - (Jt) -1,2-Diaminocyclohexane lolatinate) (1-methyl-2-20 oxoacetidine-4,4-dicarboxylate)

Following the procedure described in Example 1, 0.09 g of the title compound was prepared from 0.399 g of cis- (trans- (i) -1,2-diaminocyclohexane] platinum (II) dinitrate and 0.2 g of sodium 1-methyl- 2-oxoate-25 cetidine-4,4-dicarboxylate (prepared as described in Preparation 1).

. . Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.2 (4H, multiplet); 1.4 (2H, doublet); 1.85 (2H, doublet); 2.2 (2H, broad singlet-like); 2.80 (3H, singlet); • 3.63 (2H, singlet).

35 EXAMPLE 4 36 S7572 cis- trans - (E) -1,2-Diaminocyclohexane 1 platinum (II1) (1,3-dimethyl-2-oxoacetidine-4,4-dicarboxylate) 5

A solution of 0.2 g of 1,3-dimethyl-2-oxoazetidine-4,4-dicarboxylic acid in 5 ml of water was added to a solution of 0.3 g of cis- [trans- (E) -1,2- diaminocyclohexane] dihydroxyplatinum (II) dissolved in 10 ml of water. The mixture was then stirred at room temperature for 10 hours. After this time, water was stripped from the mixture by evaporation under reduced pressure, and the residue was stirred with acetone to effect crystallization. The resulting crystals were collected by filtration and washed with acetone to give 0.31 g of the crude title compound. This was dissolved in water and purified by column chromatography through a column containing Sephadex LH-20 (eluting with water) to give 0.17 g of the title compound.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9 - 1.2 (4H, multiplet); 1.38 (2H, doublet); 1.54 and 1.59 (together 3H, each doublet, J-7 Hz); 1.85 (2H, doublet); 2.74 and 2.75 (together 3H, each singlet); • - 3.61 and 3.64 (together 1H, each quartet, J-7 Hz).

EXAMPLE 5 cis-trans ((E) -1,2-Diaminocyclohexane-platinum (II) 2-oxo-pyrrolidine-5,5-dicarboxylate) 30 440 mg of sodium 2-oxopyrrolidine-5,5-dicarboxylate (prepared as described in Preparation 2) was added. to a solution of 866 mg of cis-f trans- (1) -1,2-diaminoscyclohexanylplatinum (II) dinitrate in 70 ml of water and the mixture was kept at 26 ° C for 7 hours. After this time, the precipitated crystals were collected by filtration and washed with water to give 219 mg of the title compound as colorless crystals. The filtrate was then concentrated to a volume of 40 ml by evaporation under reduced pressure and allowed to stand at 26 ° C. The resulting crystals were then treated in the same manner as described above to give an additional 170 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.87-1.23 (AH, multiplet); 1.32 - 1.48 (2H, multiplet); 1.81-1.95 (2H, multiplet); 2.15 - 2.30 (2H, multiplet); 2.31 (2H, triplet, J = 7.9 Hz); 3.14 - 3.32 (2H, multiplet).

Infrared Absorption Spectrum (KBr) ν max cm -1: 1709, 1671, 1630.

EXAMPLE 6 cis-trans (1- (1,2-Diaminocyclohexane) platinum (II) (3-isopropyl-2-oxoacetidine-4,4-dicarboxylate))

Following a procedure similar to that described in Example 1, 260 mg of the title compound was prepared from 707 mg of cis-itrans- (i) -1,2-diaminocyclohexane] platinum (II) dinitrate and 400 mg of 3-isopropyl-2-oxoazetidine-4. 4-dicarboxylate.

25

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.79 (3H, doublet, J-6.6 Hz); : 0.9-1.05 (2H, multiplet); 1.0 - 1.2 (2H, multiplet); 1.16 (3H, doublet, J-7 Hz); 1.3-1.45 (2H, multiplet); 1.8-1.9 (2H, multiplet); 2.1 - 2.35 (2H, multiplet); 2.76 (3H, singlet); 35 3.05-3.2 (1H, multiplet); 3.47 (1H, doublet, J = 3.3 Hz).

38 87 572 EXAMPLE 7 cis- (trans - (E) -1,2-Diaminocyclohexanylplatinum) (1-methyl-3-isopropyl-2-oxoacetidine-4,4-dicarboxylate) 5

Following a procedure similar to that described in Example 1, 660 mg of the title compound was prepared from 1.3 g of cis-trans-1,2-diaminocyclohexane] platinum (II) dinitrate and 780 mg of sodium 1-methyl-3-isopropyl-2-oxoacetidine. -4,4-dicarboxylate.

10

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.81 (3H, doublet, J = 7 Hz); 0.9-1.2 (4H, multiplet); 1.18 (3H, doublet, J-7 Hz); Δ 1.35-1.45 (2H, multiplet); 1.8-1.95 (2H, multiplet); 2.05 - 2.3 (2H, multiplet); 2.76 (3H, singlet); 3.05-3.2 (1H, multiplet); 3.51 (1H, doublet, J = 4Hz).

EXAMPLE 8 '' · cis-trans- (1) -1,2-Diaminocyclohexanylplatinum (II) (1-methoxymethyl-2-oxoacetidine-4,4-dicarboxylate)

Following a procedure similar to that described in Example 1, 200 mg of the title compound was prepared from 500 mg of cis-Γtrans- (I) -1.2-. . diaminocyclohexane] platinum (II) dinitrate and 280 mg of sodium Ι- ΙΟ methoxymethyl-2-oxoazetidine-4,4-dicarboxylate.

. Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.85 - 1.2 (4H, multiplet); 1.3-1.45 (211, multiplet); 35 1.8-1.9 (211, multiplet); 2.1-2.3 (2H, multiplet); 3.24 (3H, singlet); 39 87572 3.76 (2H, singlet); 4.57 (2H, singlet).

EXAMPLE 9 5 cis- (trans- (2) -1,2-Diaminocyclohexanylplatinum) II 1- (2-methoxy-ethoxy) methyl-2-oxoacetidine-4,4-dicarboxylate1

Following a procedure similar to that described in Example 1, 135 mg of the title compound was purified from 300 mg of cis-f trans - (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 200 mg of sodium 1- (2-methoxyethoxy) methyl-2-oxoazetidine-4,4-dicarboxylate.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.2 (4H, multiplet); 1.35 - 1.45 (2H, multiplet); 1.8-1.9 (2H, multiplet); 2.15 - 2.3 (2H, multiplet); 3.19 (3H, singlet); Δ 3.4-3.47 (2H, multiplet); 3.6-3.65 (2H, multiplet); 3.76 (2H, singlet); 4.66 (2H, singlet).

EXAMPLE 10 cis-trans (1- (1,2-Diaminocyclohexane) platinum) (1-roethoxymethyl-3-isopropyl-2-oxoacetidine-4,4-dicarboxylate) 30 Following a similar procedure to that described in Example 1, 630 mg of the title compound was prepared from 750 mg of the title compound: -f trans- (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 500 mg of sodium 1-methoxymethyl-3-isopropyl-2-oxoazetidine-4,4-dicarboxylate.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.81 (3H, doublet, J = 5.5 Hz); . . 0.9-1.25 (4H, multiplet); 40 8 7 5 7 2 1.16 (3H, doublet, J-7 Hz); 1.3 - 1.45 (2H, multiplet); 1.8-1.9 (2H, multiplet); 2.1 - 2.35 (2H, multiplet); Δ 3.23 (3H, singlet); 3.1-3.3 (1H, multiplet); 3.58 (1H, doublet, J = 3.3 Hz); 4.45 (1H, doublet, J-12 Hz); 4.62 (1H, doublet, J-12 Hz).

EXAMPLE 11 cis-f trans- (d) -1,2-Diaminocyclohexanylplatinum (II) 2-oxoacetidine-4,4-dicarboxylate 15

Following a procedure similar to that described in Example 1, 125 mg of the title compound was prepared from 500 mg of cis-trans (d) -1,2-diaminocyclohexane] platinum (II) dinitrate and 234 mg of sodium 2-oxoacetidine-4,4-dicarboxylate.

20

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.1 (4H, multiplet); 1.3-1.45 (2H, doublet); 1.8-1.9 (2H, doublet); 2.1-2.3 (2H, multiplet); 3.74 (2H, singlet).

EXAMPLE 12 cis-Diammineplatinum (II) (1-methyl-3-isopropyl-2-oxoazetidine; 4,4-dicarboxylate)

Following a procedure similar to that described in Example 2, 200 mg of the title compound was prepared from 400 mg of cis-diamine platinum-35 (II) dinitrate and 300 mg of sodium 1-methyl-3-isopropyl-2-oxoacetidine-4,4-dicarboxylate.

i 4i 87572

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.88 (3H, doublet, J- = 6.3 Hz); 1.22 (3H, doublet, J = 6.8 Hz); 2.81 (3H, singlet); Δ 2.7-2.9 (1H, multiplet); 3.40 (1H, doublet, J -3 Hz); 4.2 (6H, broad singlet).

EXAMPLE 13 10 cis-Diammineplatinum (II) (1-methoxymethyl-2-oxoacetidine-4,4-dicarboxylate)

Following a procedure similar to that described in Example 2, 105 mg of the title compound was prepared from 200 mg of cis-diamine platinum (II) dinitrate and 134 mg of sodium 1-methoxymethyl-2-oxoacetidine-4,4-dicarboxylate.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: δ 3.31 (3H, singlet); 6.67 (2H, singlet): 4.24 (6H, broad singlet); 4.60 (2H, singlet).

EXAMPLE 14: cis- [trans- (E) -1,2-Diaminocyclohexanyl] platinum (111 ((3S, 4R1 -3-f (R1-1-t-butylmethyl) methyloxyethyl) -2-oxoacetidin-4-yl) acetate 30 L .9 g of cis-trans ((1) -1,2-diaminoscyclohexanedihydroxyplatinum (II) dinitrate were suspended in 100 ml of water and the suspension was stirred overnight at 28. After this time, a solution of (3S, 4R) was added to the reaction mixture. ) -3 - [(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-ylacetic acid dissolved in 2 equivalents of aqueous sodium hydroxide solution and crystals immediately precipitated, which were collected by filtration, washed with water and dried to give 42 37572 l. 6 g of the title compound as a pale yellow powder.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.09 (3H, singlet); Δ 0.10 (3H, singlet); 0.90 (9H, singlet); 1.1-1.4 (2H, raultiplet); 1.29 (3H, doublet, J = 6.5 Hz); 1.5-1.8 (2H, multiplet); Δ 1.9-2.2 (2H, multiplet); 2.2-2.4 (2H, multiplet); 2.45 (1H, doublet of doublets, J-14 & 10 Hz); 2.57 (1H, doublet of doublets, J-14 & 5.5 Hz); 2.86 (1H, doublet of doublets); Δ 4.09 (1H, multiplet); 4.29 (1H, multiplet).

EXAMPLE 15 cis- [trans - (dl -1,2-Diaminocyclohexane] platinum (II) I (3S, 4R) -3 - [(R) -1-t-butylmethyl] methyloxyethyl-2-oxoacetidin-4-ylacetate

Following a procedure similar to that described in Example 14, 1.56 g of the title compound was prepared from 1.9 g of cis-f trans- (d) -1,2-diaminocyclohexane] platinum (II) dinitrate.

: Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.09 (3H, singlet); Δ 0.10 (3H, singlet); 0.90 (9H, singlet); 1.1-1.4 (2H, multiplet); 1.23 (3H, doublet, J = 6.3 Hz); 1, 5-1, 8 (211, hui II IplottI)); Δ 1.9-2.2 (2H, multiplet)); 2.2-2.4 (2H, multiplet); 2.4-2.7 (2H, multiplet); 43 «7572 2.84 (1H, doublet of doublets); 4.01 (1H, multiplet); 4.21 (1H, multiplet).

EXAMPLE 16 cis- [trans- (E) -1,2-Diaminocyclohexanylplatinum (II) I (3S, 4R ') -3 - [(R') -1-t-hydroxyethyl] -2-oxoazetidin-4-yl) acetate 10 866 mg of cis-trans- (1) -1,2-diaminoscyclohexanylplatinum (II) dinitrate were suspended in 30 ml of water, and then 350 mg of {3S, 4R) -3 - [(R) -1-hydroxyethyl] -2-oxoacetide was added to the suspension. -4-ylacetic acid and 2 equivalents of 1N aqueous sodium hydroxide solution. The mixture was then stirred at room temperature for 18 days. After this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through a column containing CHP-20P resin, eluting with water to give 100 mg of the title compound as a colorless powder.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.8-1.3 (4H, multiplet); 1.12 (3H, doublet, J = 6.2 Hz); 1.3-1.5 (2H, multiplet); 1.8-2.0 (2H, multiplet); 2.1-2.5 (5H, multiplet); 3.48 (1H, multiplet); 4.5 (1H, multiplet).

EXAMPLE 17 cis-trans ((1) -1,2-Diaminocyclohexanylplatinum (II) ((3S, 4R) -3-i (R) -1- (methoxymethoxy) ethyl) -2-oxoazetidine-4-yl acetate

Following a procedure similar to that described in Example 16, 64 mg of the title compound was prepared from 199 mg of cis-f trans- (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 100 mg of (3S, 4R) -3- [(R) -1- (Methoxymethoxy) ethyl] -2-oxoazetidin-4-ylacetyl-44 H 7 57? acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.1 (4H, multiplet); Δ 1.07 (3H, doublet, J-6 Hz); 1.3-1.5 (2H, multiplet); 1.8-1.9 (2H, multiplet); 2.1-2.2 (2H, multiplet); 2.35 (1H, doublet of doublets, J-15 & 8 Hz); Δ 2.41 (1H, doublet of doublets, J-15 & 6 Hz); 2.91 (1H, doublet of doublets, J = 5.2 Hz); 3.19 (3H, singlet); 3.76 (1H, doublet of doublets, J = 8.6 & 2 Hz); 3.95 (1H, quartet, doublet, J-6 & 5 Hz).

EXAMPLE 18 cis-trans- (E) -1,2-Diaminocyclohexanylplatinum (II) ((3S, 4R) -3-f (R) -1- (methoxyethoxymethoxy) ethyl) -2-oxoacetidin-4-yl) acetate 20

Following a procedure similar to that described in Example 16, 83 mg of the title compound was prepared from 166 mg of cis-f trans- (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 100 mg of (3S, 4R) -3 - [(R ) -1- (2-methoxyethoxymethoxy) ethyl] -2-oxoazetidin-4-ylacetic acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.8-1.2 (4H, multiplet); 1.07 (3H, doublet, J-6.6 Hz); Δ 1.3-1.5 (2H, multiplet); 1.7-1.9 (2H, multiplet); 2.1-2.2 (2H, multiplet); 2.35 (1H, doublet of doublets, J-15 & 8 Hz); 2.40 (1H, doublet of doublets, J-15 & 6 Hz); 35 2.91 (1H, doublet of doublets, J = 4.4 & 1.8 Hz); 3.19 (3H, singlet); n. 3.45 (2H, multiplet); i f rj r- n o 45 H / 5 / / n. 3.54 (2H, multiplet); 3.75 (1H, doublet of triplets, J = 2.2 & 5.8 Hz); 3.98 (1H, doublet of quartets).

5 EXAMPLE 19 cis-Γ trans- (2) -1,2-Diaminocyclohexane-platinum (II) ((3S, 4R) -3-Γ (R) 1-diethylphosphonoxy) methyl 2 -2-oxoacetidin-4-yl acetate 10 Following a procedure similar to that described in Example 16 was prepared from 27 mg of the title compound from 188 mg of cis-f trans - (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 150 mg of (3S, 4R) -3 - [(E) -1-dietyylifosfonoksietyyli] -2-oxoazetidin-4-yl-acetic acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9 - 1.2 (4H, multiplet); 1.10 (4H, doublet of doublets, J-7, 20 Hz); 1.24 (3H, doublet, J-7 Hz); 1.3-1.5 (2H, multiplet); Δ 1.8-1.9 (2H, multiplet); 2.1-2.2 (2H, multiplet); 2.37 (1H, doublet of doublets, J-7 & 14 Hz); 2.42 (1H, doublet of doublets, J-6 & 14 Hz); 3.02 (1H, doublet of doublets, J-2 & 6 Hz); 3.73 (1H, quintet, J-7 Hz); 3.86 (1H, doublet of triplets, J-2 & 6 Hz); 3.9-4.1 (4H, multiplet).

EXAMPLE 20 30: cis-itrans- (E) -1,2-Diaminocyclohexane-platinum III ((3S, 4R-3-f (R) -1-diphenylphosphonooxyethyl) -2-oxoacetidin-4-yl acetate)

Following a procedure similar to that described in Example 16, 101 mg of the title compound was prepared from 107 mg of cis-itrans-η 1 -2-diaminocyclohexane] platinum (II) distillate and 100 mg of (3S, 4R) -3 - [( R) -1-Diphenylphosphonooxyethyl] -2-oxoazetidin-4-ylacetic acid * 6 S 7 S 7 2 poa.

Yrununagnetic resonance spectrum (270 MHz, D 2 O) δ ppm: 0.8-1.2 (4H, multiplet); Δ 1.27 (3H, doublet, J = 6 Hz); 1.3-1.5 (2H, multiplet); 1.7-2.0 (2H, multiplet); 2.0 - 2.3 (2H, multiplet); 2.27 (2H, multiplet); Δ 3.00 (1H, doublet of doublets, J-3 & 7 Hz); 3.73 (1H, doublet of triplets, J = 2 & 8 Hz); 4.93 (1H, multiplet); 7.0-7.4 (10H, multiplet).

EXAMPLE 21 cis-trans- (1) -1,2-Diaminocyclohexanylplatinum (II) tert-butylmethylsulfonyloxyethyl -2-oxoacetidin-4-yl

Following a procedure similar to that described in Example 14, 0.16 g of the title compound was prepared from 0.19 g of cis-f trans- (E) -1,2-diaminocyclohexane] platinum (II) dinitrate and 0.13 g of 3S, 4S) -3 - [(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidine-4-25 carboxylic acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm:: 0.05 (3H, singlet); 0.09 (3H, singlet); Δ 0.90 (9H, singlet); 1.1-1.4 (4H, multiplet); 1.29 (3H, doublet, J-7Hz); 1.5-1.8 (2H, multiplet); 1.95 - 2.15 (2H, multiplet); Δ 2.2-2.4 (2H, multiplet); 3.13 (1H, triplet, J = 2 Hz); 4.10 (1H, doublet, J-2 Hz); 1 A7 87572 4.30 (1H, doublet of quartets, J = 7.2 Hz).

EXAMPLE 22 5 cis- Γ trans - (2) -1,2-Diaminoscyclohexane 1 platinum (II) IC3S. 4S) -3 - [(R) -1-Octanoyloxyethyl] -2-oxoazetidine-4-ylcarboxylate 228 mg of cis-trans - (i) -1,2-diaraocyclohexane] platinum (II) dinitrate were suspended in 10 ml of water and the suspension was stirred at 26 ° C for 3 to 10 hours to form a homogeneous solution. After this time, 1.05 ml of 1N aqueous sodium hydroxide solution and 150 mg of (3R, 4S) -3 - [(R) -1-octanoyloxyethyl] -2-oxoazetidine-4-carboxylic acid were added to the solution, and the resulting mixture was then stirred at room temperature for 1 hour. 5 hours. The precipitated crystals were collected by filtration and washed with water, acetone and diethyl ether, respectively, to give 84 mg of the title compound. Additional crystals precipitated from the mixture of filtrate and washings after allowing the mixture to stand for 2 days at room temperature. The resulting crystals were collected by filtration and washed with water, acetone and diethyl ether, respectively, to give an additional 12 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.65 (3H, triplet, J-6 Hz); 0.8-1.15 (12H, multiplet); 1.17 (3H, doublet, J-6 Hz); 1.3-1.5 (4H, multiplet); ·: 1.7-1.85 (2H, doublet-like); : 1.95-2.1 (2H, multiplet); 2.1-2.3 (2H, multiplet); 3.20 (1H, triplet, J-3 Hz); : 3.95 (1H, doublet, J-3 Hz); 5.05-5.2 (1H, multiplet).

mn j- Γ7 48 "5/2 EXAMPLE 23 cis- Γ trans - (13 -1,2-Diaminocyclohexanil platinum (II) ((3S, 4S3-3-f 1- (R ~) -hydroxyethyl] -2-oxoacetidin-4 -wli) carboxylate 5

Following a procedure similar to that described in Example 16, 186 mg of the title compound was prepared from 594 mg of cis- [trans- (i) -1,2-diaminocyclohexane] platinum (II) dinitrate and 218 mg of (3S, 4S) -3- [ (R1-hydroxyethyl] -2-oxoazetidine-4-carboxylic acid (prepared as described in Preparation 3).

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.2 (4H, multiplet); 1.10 (3H, doublet, J-7 Hz); 1.3-1.5 (2H, multiplet); 1.7-2.0 (2H, multiplet); 2.1-2.3 (2H, multiplet); 3.02 (1H, doublet of doublets, J-3 & 4 Hz); 3.85 (1H, doublet, J -3 Hz); 4.04 (1H, doublet of quartets, J-4 & 7 Hz).

EXAMPLE 24 'cis-f trans - (i) -1,2-Diaminocyclohexanylplatinum (III (4S) -2-oxoacetidine-4-carboxylate 735 m cis-f trans- (t) -1.2-diaminoscyclohexanylplatinum (II) dinitrate was suspended To 50 ml of water and 230 mg of (4S) -2-oxoazetidine-4-carboxylic acid and 1.8 ml of 1N aqueous sodium hydroxide solution were added -30 to the suspension, which was then stirred at 28 ° C for 4 days. was concentrated by evaporation under reduced pressure, and then acetone was added to the residue to precipitate crystals, which were collected by filtration, washed with water and acetone, and dried under reduced pressure to give 195 mg of the title compound.

35

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.9-1.2 (4H, multiplet); 49 8757? 1.3-1.5 (2H, multiplet); 1.8-2.0 (2H, multiplet); 2.1-2.3 (2H, multiplet); 2.43 (1H, doublet of doublets, J = 4.0 & 17.2 Hz); Δ 2.52 (1H, doublet of doublets, J = 6.6 & 17.2 Hz); 3.58 (1H, doublet of doublets, J = 4.4 & 6.6 Hz).

EXAMPLE 25 cis-Itrans- (i) -1,2-Diaminocyclohexanylplatinum (II) ((3S, 4R) -3-f (R) -1-octanoyloxyethyl) -2-oxoazetidin-4-yl acetate

Following a procedure similar to that described in Example 16, 100 mg of the title compound was prepared from 579 mg of cis- [trans- (i) -1,2-15 diaminocyclohexane] platinum (II) dinitrate and 400 mg of [(3S, 4R) -3 - (R) -1-oktanoyylioksietyyli) -2-oxoazetidin-4-yl] acetate.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.68 (3H, triplet, J = 7 Hz); Δ 0.8-1.2 (10H, multiplet); 1.14 (3H, doublet, J-6 Hz); 1.25-1.5 (4H, multiplet); 1.7-2.0 (2H, multiplet); 2.1-2.3 (2H, multiplet); 2.40 (2H, doublet, J = 7.5 Hz); 3.03 (1H, doublet of doublets, J-4 & 2 Hz); 3.86 (1H, doublet of triplets, J-2 & 7.5 Hz); 5.08 (1H, doublet of quartets, J-4 Hz).

EXAMPLE 26 cis-trans- (E) -1,2-Diaminocyclohexanylplatinum II) (3S, 4S) -3-f (R) -1-hexanoyloxyethyl] -2-oxoacetidine-4-carboxylate 35 Following a procedure similar to that described in Example 22. 100 mg of the title compound was prepared from 274 mg of cis- [trans - (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 218 mg of (3S, 4S) - • 7 *** Γ7, ·> 50 j / ν 1 - [(R) -1-Hexanoyloxyethyl] -2-oxoazetidine-4-carboxylic acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.68 (3H, triplet, J-7 Hz); Δ 0.8-1.25 (8H, multiplet); 1.18 (3H, doublet, J = 6.4 Hz); 1.3-1.5 (4H, multiplet); 1.75-1.95 (2H, multiplet); 1.95 - 2.05 (2H, multiplet); Δ 2.1-2.35 (2H, multiplet); 3.21 (1H, doublet of doublets, J = 3.7 & 2.5 Hz); 3.97 (1H, doublet, J = 2.5 Hz); 5.13 (1H, doublet of quartets, J = 3.7 & 6.4 Hz).

EXAMPLE 27 cis-trans - (1) -1,2-Diaminocyclohexane-platinum (ID C3S. 4S) -3-Γ (R) -1-butanoyloxyethyl 1-2-oxoazetidine-4-carboxylate 20 Following the same procedure as in Example 22. described, 100 mg of the title compound was prepared from 210 mg of cis- [trans- (E) -1,2-diaminocyclohexane] platinum (II) dinitrate and 150 mg of (3S, 4S) -3 - [(R) -1 -butanoyloxyethyl] -2-oxoazetidine-4-carboxylic acid.

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.71 (3H, triplet, J = 7.5 Hz); · 0.85-1.15 (4H, multiplet); 1.18 (3H, doublet, J-6.6 Hz); • ·: 1.25-1.4 (2H, multiplet); Δ 1.3-1.5 (2H, multiplet); . : 1.75-1.85 (2H, multiplet); . 1.95 - 2.05 (2H, multiplet); 2.1-2.3 (2H, multiplet); 3.21 (1H, doublet of doublets, J = 3.6 & 2.3 Hz); 35 3.96 (1H, doublet, J-2.3 Hz; 5.14 (1H, doublet of quartets, J-3.6 & 6.6 Hz).

51 8 7 57 2 ESTHERKET? 8 cis- (cis-1,2-Diaminocyclohexanylplatinum (II) (3S, 4S) -3-f (R) -1-octanoyloxyethyl 2-oxoacetidine-4-carboxylate 5

Following a procedure similar to that described in Example 22, 40 mg of the title compound was prepared from 300 mg of cis-trans - (1) -1,2-diaminocyclohexane] platinum (II) dinitrate and 197 mg of (3S, 4S) -3 - [(E ) -1-oktanoyylioksietyyli] -2-oxoazetidine-4-carboxylic acid.

10

Nuclear Magnetic Resonance Spectrum (270 MHz, D 2 O) δ ppm: 0.90 (3H, triplet, J-7 Hz); 1.25 - 1.45 (10H, multiplet); 1.39 (3H, doublet, J = 6.6 Hz); 1.55-1.75 (4H, multiplet); 1.75-1.9 (4H, multiplet); 2.25 - 2.4 (2H, multiplet); 2.6-2.7 (2H, multiplet); 3.42 (1H, doublet of doublets, J = 4.7 & 2.5 Hz); 3.99 (1H, doublet, J = 2.5 Hz); 5.31 (1H, doublet of quartets, J-4.7 & 6.6 Hz).

PREPARATION 1 Sodium 2-oxoacetidine-4,4-dicarboxylate 1 (a) A solution of 6.11 ml of bromoacetyl chloride in 60 ml of tetrahydrofuran was added to a solution of 24 g of diethyl N- (2,4-dimethoxybenzyl) aminomalonate 120 in tetrahydrofuran, while cooling with ice, and then 10.3 ml of triethylamine was added dropwise to the resulting mixture. The mixture was stirred for 2 hours under ice-cooling, after which the precipitated crystals were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and water, respectively. It was then liberated from ethyl acetate by evaporation under reduced pressure to give 31.5 g of an oily product. All this oil was dissolved in 200 ml of benzene and the resulting solution was mixed with 11.2 ml of triethylamine. The mixture was then stirred overnight at room temperature, after which it was diluted with ethyl acetate. The mixture was then washed with dilute aqueous hydrochloric acid solution, aqueous sodium bicarbonate solution and water, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (400 g), eluting with a 1: 5 by volume mixture of ethyl acetate and benzene to give 21 g of diethyl 1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4,4-dicarboxylate.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 1.16 (6H, triplet, J-7 Hz); 3.32 (2H, singlet); 3.78 (6H, singlet); 4.02 (4H, quartet, J-7 Hz); 4.57 (2H, singlet); 6.4 (2H, singlet); Δ 7.1 (1H, multiplet).

1 (b) 17.4 g of diethyl 1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4,4-dicarboxylate (prepared as described above) was dissolved in a mixture of 350 ml of acetonitrile and 350 ml of water. To the resulting solution were added 11.2 g of potassium persulfate and 37.4 g of dibasic potassium phosphate, and the mixture was stirred at 65 ° C for 1 hour. After this time, insoluble materials were filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, respectively. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and benzene, to give 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: δ 53 8 7 5 7 2 1.28 (6H, triplet, J-7 Hz); 3.38 (2H, doublet-like, J-2 Hz); A, 26 (All, quartet, J-7 Hz); 7.2 (1H, broad singlet).

5 L (c) 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate (prepared as described above) was dissolved in 25 ml of methanol. To the resulting solution was added 53.2 ml of 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 day. After this time, the reaction mixture was concentrated by evaporation under reduced pressure to give crystals, which were washed with methanol and diethyl ether to give 5.3 g of the title compound as crystals.

PREPARATION 2 15

Sodium 2-oxopyrrolidine-5,5-dicarboxylate 2 (a) 2.8 ml of triethylamine was added to a suspension of 2.11 g of diethyl 2-aminomalonate hydrochloride in 50 ml of methylene chloride.

Then, 1.71 g of 3-bromopropionyl chloride was added to the mixture while cooling with ice, and then the mixture was stirred for 30 minutes. After this time, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous sodium bicarbonate solution and water, respectively, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to give 2.5 g of diethyl 2- (3-bromopropionamido) malonate.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 1.28 (6H, triplet, J = 7.0 Hz); 2.87 (2H, triplet, J = 6.6 Hz); 3.61 (2H, triplet, J = 6.5 Hz); 4.25 (4H, quartet, J = 7.0 Hz); 5.14 (1H, doublet, J = 7.0 Hz); 6.65 (1H, broad singlet).

354 (b) 314 μΐ of 1,8-diaza [5.4.0] -7-undecene was added to a solution of 620 mg of diethyl 2- (3-bromopropionamido) malonate (prepared as 54,37572 as described above) dissolved in methylene chloride, and the mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was concentrated by evaporation under reduced pressure, poured into water and then extracted with diethyl ether. The extract was washed with 5% w / w aqueous hydrochloric acid, 5% w / w aqueous sodium bicarbonate and water, respectively, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to give the crude product. This was purified by column chromatography through silica gel, eluting with a 2: 1 by volume mixture of cyclohexane and ethyl acetate to give 171 mg of diethyl 2-oxopyrrole-dinin-5,5-d i carboxy 1 aa t t Ia.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 1.28 (6H, triplet, J = 7.0 Hz); 2.2-2.8 (4H, multiplet); 4.25 (4H, quartet, J = 7.0 Hz); 7.5 (1H, broad singlet).

2 (c) 8.74 ml of 1N aqueous sodium hydroxide solution was added to a solution of 1.0 g of diethyl 2-oxopyrrolidine-5,5-dicarboxylate (prepared as described above) in 10 ml of ethanol, and the mixture was stirred at room temperature for 3 days. . After this time, the solvent was removed by distillation under reduced pressure, and the residual crystals were washed with acetone and dried to give 950 mg of sodium 2-oxopyrrolidine-5.5-25 dicarboxylate as a colorless powder.

f Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 2.35 (broad singlet).

Infrared Absorption Spectrum (KBr) λmax 1: 3180, 1700, 1630.

PREPARATION 3

1 '»1-1 (Kiri-Hyc.lr.vkslet yyU J - 2: <.> Kso <jl« et J <1J JLlll-tkskaxy 1 HuUiP.Q

3 (a) 14 g of benzyl 1- (2,4-dimethoxybenzyl) -3 - [(R) -1-hydroxyethyl 55,87572] -2-oxoacetidine-4-carboxylate [synthesized by a procedure similar to that described in Tetrahedron 46, 1975 (1984)] was dissolved in a mixture of 420 ml of acetonitrile and 420 ml of water. To the solution were added 66.1 g of potassium persulfate and 23.3 g of dibasic potassium phosphate, and the mixture was stirred at 70 ° C for 60 minutes. After this time, insolubles were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and freed from the solvent by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give 6.1 g of benzyl 3 - [(R) -1-hydroxyethyl] -2-oxoazetidine-4-carboxylate.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 1.26 (3H, doublet, J = 6.0 Hz); 3.19 - 3.45 (2H, multiplet); 3.93-4.49 (1H, multiplet); 4.30 (1H, doublet, J = 3.0 Hz); 5.17 (2H, singlet); Δ 6.88 (1H, singlet); 7.33 (5H, singlet).

3 (b) 500 mg of benzyl 3 - [(R) -1-hydroxyethyl] -2-oxoazetidine-4-carboxylate (prepared as described above) was dissolved in 5 ml of methanol and the mixture was hydrogenated so that 10% by weight of palladium on carbon was present as a catalyst at room temperature for 2 hours, after which time the catalyst was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure to give 310 mg of the title compound as a colorless oil.

30

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl 3) δ ppm: 1.27 (3H, doublet, J = 6.0 Hz); 3.2-3.4 (1H, multiplet); 4.23 (1H, doublet, J = 3.0 Hz); 35 4.0-4.35 (1H, multiplet); 8.07 (1H, broad singlet).

56 87572

TEST

The experimental animals used in the next experiment were 8-9 week old female CDFi mice each weighing 20-20-25 g. Standard L1210 leukemia cells were provided by Dr. T. Yamoto,

Institute of Medical Science, University of Tokyo, Japan.

CDF1 mice were vaccinated intravenously with L1210 cells (105 cells / mouse). The test compound is as identified in Table 6 below. In the case of the compounds of the present invention and carboplatin, this was dissolved in a 5% by volume aqueous solution of mannitol, while cisplatin was dissolved in a 5% by volume solution of mannitol in physiological salt. Each drug was injected intravenously on days 1 and A after tumor implantation. The number of mice in each experiment was 6.

15

Life expectancy growth (ILS) was calculated as follows: ILS% - [(St / Su) -1] x 100 20 where:

St - weighted average number of survival days of treated mice; and 25 Su - the weighted average number of survival days of untreated mice.

The results are shown in Table 6.

30 57 87 572

Table 6

Compound Dose Weight- ILS Survive 5 of them (mg / kg) change (g) (%) on day 42 1) 2) Untreated control - +1.9 - 0/6

Compound 20 of Example 1 10 +1.0> 196 4/6 20 -0.2> 198 6/6 40 -0.2> 196 4/6 15 80 -1.2> 197 5/6

Example 14 2.5 -0.3> 230 5/6 compound 5 -0.3> 231 6/6 10 -1.5> 231 6/6 20 20 -5.5 40 0/6

Carboplatin 5 +1.3 7 0/6 10 +2.0 7 0/6 20 +0.8 7 0/6 25 40 +0.4 10 0/6 • 80 -0.5 23 0/6 cisplatin 1 , 25 +2.7 19 0/6 2.5 + 0.7 82 0/6 30 5 -2.2 254 3/6

Notes: 35 1) Change in body weight from day 1 to day 7.

2) Growth in life expectancy.

Claims (20)

58 87572 An analogous process for the preparation of a therapeutically active platinum complex of the formula (I): ; 20 and Z represent a group of formula (II): O // OC (CH 2> a / \ / \ 25. CH-R1 (ID \ / \ / 0-C N-c Λ | NN O S2 o 3. or a group of formula (III): O-C / N „* (III) N-C- H I I C-CH a \ o r! 59 87572: R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a substituted C 1 -C 4 alkyl group having at least one of the following substituents selected from hydroxy groups, silyloxy groups having 1 -3 C 1 -C 4 alkyl substituents on the silicon atom, C 1 -C 4 alkoxy groups, -OPO (OR 3) 2 of the formulas in which R 3 represents a C 1 -C 4 alkyl group or a phenyl group and -O-C 0 R 4 groups in which R * represents A C 1 -C 8 alkyl group, a C 2 -C 5 alkoxyalkoxy group and a C 3 -C 7 alkoxyalkoxyalkoxy group; R 2 represents a hydrogen atom, a C 1 -C 4 alkyl group, a substituted C 1 -C 4 alkyl group having at least one of the substituents selected from C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups and C 2 -C 5 alkyl groups. alkoxyalkoxy groups, X represents a single carbon-carbon bond or a methylene group; 20. is 0 or 1; characterized in that the method comprises a compound of formula (Va): 25 A Ra \ / Pt / V CVa) 30. Reacting Ha (wherein A and B are as defined above and R * represents a hydroxy group or a nitrooxy group) with a compound of formula (VI), (VII) or (IX): 60 8 7 5 7 2 MOOC CCH2) a W \ c CH-a1 (vi) 5 / '/ 5 MOOC N_C I W a2 o 10 X-COOH / HN-CH l L cvm C-CH // \ ο a1 15 HOOC (CH2) n \ / \ c CH-a1 Cix) / \ / 2o HOOC NC L * a2 o (where R1, R2, X and n are as defined above and M represents an alkali metal), if necessary in the presence of an alkali. 25 Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen for the preparation of a compound of formula (Ia): CH 2 R 1 (Ia) ) / \ / \ / B OC MC f-: 35 \\ | Wherein A, B, R 1, R 2 and n are as defined in claim 1. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen for the preparation of a compound of formula (Ib): A a 0-C 10 \ / Pt T / \ / B NCH II C-CH 0 \ B1 wherein A, B, R1 and X are as defined in claim 1. Method according to Claim 1 or 2, characterized in that n is 0. Method according to Claim 2, characterized in that R1 means: a hydrogen atom; C1-C4 alkyl group; a substituted C 1 -C 4 alkyl group having at least one substituent selected from (C 1 -C 3 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups and silyloxy groups having 3 substituents on a silicon atom selected from C 1 -C 4 alkyl groups; R 2 represents a hydrogen atom, an alkyl group); or a substituted C 1 -C 4 alkyl group having at least one substituent selected from C 1 -C 4 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups, and 35. is 0. Process according to Claim 2, characterized in that R 1 represents a hydrogen atom, a C 1 -C 1 -alkyl group, a substituted C 1 -C 3 -alkyl group having at least one substituent selected from C 1 -C 4 -alkyl. -C 2-5 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups and silyloxy groups having 3 substituents on the silicon atom selected from C 1 -C 4 alkyl groups; R 2 represents a hydrogen atom, a C 1 -C 2 alkyl group or a substituted C 1 -C 2 alkyl group having at least one substituent selected from C 1 -C 2 alkoxy groups and C 2 -C 5 alkoxyalkoxy groups; and n is 0. Process according to Claim 3, characterized in that R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a substituted C 1 -C 4 alkyl group having at least one of the substituents (a '' '), as defined below, the substituents (a * '') are selected from silyloxy groups having 3 substituents on the silicon atom selected from C 1 -C 4 alkyl groups, or the substituents (a '' ') are selected from C 1 -C 5 alkoxy groups, C 2 -C 5 alkoxyalkoxy- 25 groups, C3-C7 alkoxyalkoxyalkoxy groups and groups of the formulas -OPO (OR3) 2 and -O-COR * 1; when: R 3 represents a C 1 -C 3 alkyl group or a phenyl group, and. . RA represents a C1-C8 alkyl group. Process according to Claim 3, characterized in that R 1 represents a hydrogen atom, a C 1 -C 2 alkyl group, a C 1 -C 2 alkoxy group, ¢ 3 87572 a substituted C 1 -C 4 alkyl group having at least one of the substituents (VAT), as defined below; the substituents (aiv) are selected from silyloxy groups having 3 3 C 1 -C 4 alkyl substituents on a silicon atom, C 1 -C 3 alkoxy groups, C 2 -C 5 alkoxyalkoxy groups, C 3 -C 7 alkoxyalkoxyalkoxy groups and -OPO (OR 3) 2 and -O * groups; wherein: R3 represents a C1-C3 alkyl group or a phenyl group, and R * represents a C1-C8 alkyl group. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen for the preparation of the following compounds: 1,2-diaminocyclohexane platinum (II) 2-oxoazetidine-4,4-dicarboxylate; 1,2-diaminocyclohexane platinum (II) (1-methyl-2-oxoazetidine-4,4-dicarboxylate); 1,2-diaminocyclohexane platinum (II) (1-methoxymethyl-2-oxoacetidine-4,4-dicarboxylate); 1,2-diaminocyclohexaneplatinum (II) [1- (2-methoxyethoxy) methyl-2-. · Oxoacetidine-4,4-dicarboxylate]; 1,2-diaminocyclohexane platinum (II) (1-methyl-3-isopropyl-2-oxoazetidine-4,4-dicarboxylate); 1,2-diaminocyclohexaneplatinum (II) 3- [1- (methoxymethoxy) ethyl] -2-35 oxoazetidin-4-yl acetate; 1,2-diaminocyclohexaneplatinum (II) 3- [1- (2-methoxyethoxymethoxy) -64,87572 ethyl] -2-oxoazetidin-4-yl acetate; 1,2-diaminocyclohexaneplatinum (II) 3- (1-octanoyloxyethyl) -2-oxoazetidin-4-ylcarboxylate; 5 or 1,2-diaminocyclohexaneplatinum (II) 3- (1-t-butyldimethylsilyloxy-ethyl) -2-oxoazetidin-4-ylcarboxylate. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen for the preparation of the following compounds: cis-f trans - (i) -1,2-diaminocyclohexane] platinum (II) 2-oxoazetidine-4.4 dicarboxylate; cis- [trans- (1) -1,2-diaminocyclohexane] platinum (II) (1-methyl-2-oxoazetidine-4,4-dicarboxylate); Cis-trans - (1) -1,2-diaminocyclohexane] platinum (II) (1-methoxymethyl-2-oxoazetidine-4,4-dicarboxylate); cis-trans - (i) -1,2-diaminocyclohexane] platinum (II) [1- (2-methoxy-ethoxy) methyl-2-oxoazetidine-4,4-dicarboxylate]; cis- [trans- (E) -1,2-diaminocyclohexane] platinum (II) (1-methyl-3-isopropyl-2-oxoazetidine-4,4-dicarboxylate); Cis-trans - (1) -1,2-diaminocyclohexane-platinum (II) {(3S, 4E) '3 - [(R) -1- (methoxymethoxy) ethyl] -2-oxoazetidin-4-yl) acetate ; cis - f trans - (1) -1. 2-diaminocyclohexane Iplatin-1) (3S, 4E) -3 - [(R) -1- (2-methoxyethoxymethoxy) ethyl] -2-oxoazetidin-4-yl [acetate; cis-trans ((1) -1,2-diaminocyclohexane] platinum (II) {(3S, 4S) -3 - [(R) -L-octanoyloxyethyl] -2-oxoazetidin-4-yl) carboxylate; : 35 65 H 7 572 or cis-trans - (1R) -1,2-diaminocyclohexane] platinum (II) {(3S, 4S) -3 - [(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidine- 4-yl Jkarbok-5 silylate. 66 87572